Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development

Sudden infant death syndrome (SIDS) cases often have abnormalities of the brainstem raphe serotonergic (5-HT) system. We hypothesize that raphe dysfunction contributes to a failure to autoresuscitate from multiple hypoxic events, leading to SIDS. We studied autoresuscitation in two transgenic mouse...

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Bibliographic Details
Published in:The Journal of neuroscience 2016-04, Vol.36 (14), p.3943-3953
Main Authors: Barrett, Karlene T, Dosumu-Johnson, Ryan T, Daubenspeck, J Andrew, Brust, Rachael D, Kreouzis, Vasileios, Kim, Jun Chul, Li, Aihua, Dymecki, Susan M, Nattie, Eugene E
Format: Article
Language:English
Subjects:
Aging - psychology
Animals
Animals, Newborn
Critical Period, Psychological
Gene Silencing
Heart Rate
Humans
Hypoxia - mortality
Hypoxia - physiopathology
Infant, Newborn
Mice
Mice, Transgenic
Raphe Nuclei - drug effects
Raphe Nuclei - physiopathology
Respiratory Mechanics
Serotonin Plasma Membrane Transport Proteins - genetics
Serotonin Plasma Membrane Transport Proteins - metabolism
Sudden Infant Death
Synaptic Transmission - drug effects
Tetanus Toxin - toxicity
Transcription Factors - genetics
Transcription Factors - metabolism
Tryptophan Hydroxylase - genetics
Tryptophan Hydroxylase - metabolism
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Summary:Sudden infant death syndrome (SIDS) cases often have abnormalities of the brainstem raphe serotonergic (5-HT) system. We hypothesize that raphe dysfunction contributes to a failure to autoresuscitate from multiple hypoxic events, leading to SIDS. We studied autoresuscitation in two transgenic mouse models in which exocytic neurotransmitter release was impaired via conditional expression of the light chain from tetanus toxin (tox) in raphe neurons expressing serotonergic bacterial artificial chromosome drivers Pet1 or Slc6a4. These used recombinase drivers targeted different portions of medullary raphe serotonergic, tryptophan hydroxylase 2 (Tph2)(+) neurons by postnatal day (P) 5 through P12: approximately one-third in triple transgenic Pet1::Flpe, hβactin::cre, RC::PFtox mice; approximately three-fourths inSlc6a4::cre, RC::Ptox mice; with the first model capturing a near equal number of Pet1(+),Tph2(+) versus Pet1(+),Tph2(low or negative) raphe cells. At P5, P8, and P12, "silenced" mice and controls were exposed to five, ∼37 s bouts of anoxia. Mortality was 5-10 times greater in "silenced" pups compared with controls at P5 and P8 (p = 0.001) but not P12, with cumulative survival not differing between experimental transgenic models. "Silenced" pups that eventually died took longer to initiate gasping (p = 0.0001), recover heart rate (p = 0.0001), and recover eupneic breathing (p = 0.011) during the initial anoxic challenges. Variability indices for baseline breathing distinguished "silenced" from controls but did not predict mortality. We conclude that dysfunction of even a portion of the raphe, as observed in many SIDS cases, can impair ability to autoresuscitate at critical periods in postnatal development and that baseline indices of breathing variability can identify mice at risk. Many sudden infant death syndrome (SIDS) cases exhibit a partial (∼26%) brainstem serotonin deficiency. Using recombinase drivers, we targeted different fractions of serotonergic and raphe neurons in mice for tetanus toxin light chain expression, which prevented vesicular neurotransmitter release. In one model, approximately one-third of medullary Tph2(+) neurons are silenced by postnatal (P) days 5 and 12, along with some Pet1(+),Tph2(low or negative) raphe cells; in the other, approximately three-fourths of medullary Tph2(+) neurons, also with some Tph2(low or negative) cells. Both models demonstrated excessive mortality to anoxia (a postulated SIDS stressor) at P5 and P8.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.1796-15.2016